Non–Cell Autonomous NK Cell Effects Underlie Combination Therapy Efficacy

Targeted anticancer therapies block tumor cell–autonomous signaling pathways, but these agents may also have tumor-extrinsic effects on host cells that could contribute to antitumor efficacy. Following previous observations that the combination of CDK4/6 and MEK inhibitors could block the proliferation of KRAS-mutant cancer cells and have immunomodulatory effects on T cells, Ruscetti, Leibold, Bott, and colleagues evaluated the non-tumor cell–autonomous effects of combined treatment with palbociclib (a CDK4/6 inhibitor) and trametinib (a MEK inhibitor) on the immune system in a syngeneic orthotopic model of Kras-mutant;Trp53-null lung cancer. No changes in macrophage infiltration or T-cell activation were observed in the lungs of treated mice, but natural killer (NK) cell accumulation was significantly increased in mice receiving combination therapy compared with single-agent treatment. Depletion of NK cells reduced the efficacy of combination but not single-agent treatment, suggesting that the efficacy of combined CDK4/6 and MEK inhibition in this model was dependent on tumor-extrinsic effects of NK cells. Palbociclib and trametinib are known to cooperate to prevent phosphorylation and inactivation of RB, which plays a key role in both cell-cycle arrest and cellular senescence. Only combination-treated tumor cells showed an increase in senescence markers and upregulation of a program of microenvironment-modulating proteins known as the senescence-associated secretory phenotype (SASP). SASP factors include secreted cytokines like TNFα that promote NK cell proliferation and activation as well as cell-surface NK adhesion modules like ICAM1, both of which were required for the antitumor efficacy of palbociclib plus trametinib in orthotopic as well as autochthonous Kras-mutant;Trp53-null lung cancer models. These findings illustrate that, in addition to their cell-autonomous effects on tumors, some targeted therapy combinations can also exert antitumor activity through restoration of senescence and NK cell–dependent immune surveillance.

Ruscetti M, Leibold J, Bott MJ, Fennell M, Kulick A, Salgado NR, et al. NK cell-mediated cytotoxicity contributes to tumor control by a cytostatic drug combination. Science 2018;362:1416–22.

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